Fig. 1: Aminochrome neurotoxicity and protective reactions.

In dopaminergic neurons, tyrosine is converted into L-dopa by tyrosine hydroxylase, forming a kind of complex with amino acid decarboxylase (AADC) and vesicular monoamine transporter-2 (VMAT-2), which is attached to the membrane of postsynaptic monoaminergic vesicles. L-dopa, inside of this complex, is converted into dopamine by AADC, which is immediately transported to the vesicles by VMAT-2. The low pH found inside the vesicles stabilizes the dopamine, such that it becomes completely stable and can be stored at high levels of concentration, preventing dopamine oxidation into ortho-quinones at a physiological pH in the cytosol. Released dopamine from dopaminergic neurons binds the dopamine receptors in the postsynaptic neurons. Later, free dopamine in the inter-synaptic space experiences the following: (i) The reuptake of dopamine is performed by the dopamine transporter (DAT), resulting in dopaminergic neurons where dopamine can be transported to the monoaminergic vesicles by VMAT-2 or can be oxidized in the cytosol. Dopamine can be degraded to 3,4-dihydroxyphenylacetaldehyde by monoamine oxidase (MAO), using a molecule of oxygen and water with a concomitant formation of NH₃ and H₂O₂. Alternatively, free dopamine in the cytosol oxidizes into dopamine o-quinone, which immediately cyclizes into aminochrome. Aminochrome can be neurotoxic by inducing the formation of neurotoxic oligomers, inducing mitochondrial dysfunction, oxidative stress, autophagy dysfunction, proteasome dysfunction, endoplasmic reticulum stress, and neuroinflammation. However, aminochrome neurotoxicity can be prevented by the two-electron reduction of aminochrome catalyzed by DT-diaphorase into leukoaminochrome, which finally forms neuromelanin in the dopaminergic neurons. (ii) Astrocytes take up the remaining dopamine, which oxidizes into dopamine o-quinone, while GSTM2 conjugates the dopamine o-quinone into 5-glutathionyl dopamine, which can later be converted into 5-cysteinyl dopamine, a stable product. Aminochrome can also be conjugated by GSTM2 into 4-S-glutathionyl-5,6-dihydroxyindoline, which is resistant to biological oxidizing agents, such as dioxygen, superoxide and hydrogen peroxide. Interestingly, aminochrome induces the overexpression of GSTM2, which can be secreted from astrocytes into the inter-synaptic space where dopaminergic neurons can internalize into the neuron cytosol. GSTM2, in the dopaminergic neuron cytosol, conjugates with glutathione both dopamine o-quinone and aminochrome. Both DT-diaphorase and GSTM2 protect the dopaminergic neurons by preventing aminochrome-induced neurotoxicity